Charged Amino Acid-rich Leucine Zipper-1 (Crlz-1) as a Target of Wnt Signaling Pathway Controls Pre -B Cell Proliferation by Affecting Runx/CBFj3-targeted VpreB and λ5 Genes

The proliferation of pre-B cells is known to further increase the clonal diversity of B cells at the stage of pre-B cells by allowing the same rearranged heavy chains to combine with differently rearranged light chains in a subsequent developmental stage, Crlz-1 (charged amino acid -rich leucine zipper-1) was found to control this proliferation of pre-B cells by working as a Wnt (wingless -related mouse mammary tumor virus integration site) target gene in these cells. Mechanistically, Crlz-1 protein functioned by mobilizing cytoplasmic CBF13 (core binding factor (1) into the nucleus to allow Runx (runt -related transcription factor)/CBF/3 heterodimerization. Runx/CBF13 then turned on its target genes such as EBF (early B cell factor), VpreB, and A5 and thereby pre -B cell receptor signaling, leading to the expression of cyclins D2 and D3. Actually, the proliferative function of Crlz-1 was demonstrated by not only Crlz-1 or beta-catenin knockdown but also Crlz-1 overexpression. Furthermore, the mechanistic view that the proliferative function of Crlz-1 is caused by relaying Wnt/(3-catenin to pre-B cell receptor signaling pathways through the regulation of Runx/CBIT heterodimerization was also verified by employing niclosamide, XAV939, and Lid as Wnt inhibitors and activator, respectively.